RU2348412C1 - Method of prevention of chronic viral hepatitis type c recurrent after virus remission - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: after primary virus remission, Ronkoleukine is introduced in dosage 500 mg with water 200 ml after supper within common interferon therapy, thus taking two courses 5-10 times every second day or 2 times a week. After the third introduction of Ronkoleukine, Likopide is additionally introduced in daily dosage 10 mg once a day within 10 days. Interval between courses is 2 months. If necessary courses are repeated.

EFFECT: prevented disease recurrence and eliminated immunodeficiency manifestation.

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Description

The invention relates to medicine, and more particularly to the field of infectology. The method is intended for the immunoprophylaxis of relapse of chronic viral hepatitis C (HVHS).

There is a standard method for the treatment of chronic viral hepatitis C with a drug from the group of α-interferons (reaferon-EC) 3 million ME 3 times a week in the muscle or under the skin for 6-12 months in the form of monotherapy or in combination with veroribavirin, which has an antiviral effect and allowing to achieve a complete response (clinical, biochemical and virological) after six months from the completion of antiviral therapy with interferon-type drugs - stable remission.

In addition to a number of side effects (cytopenic syndrome, depression, autoimmune syndrome), the disadvantage of the above method is the low efficiency of this treatment regimen, in which stable remission is observed only in 12-40% of patients [1, 3, 7].

Given the proven immune dysfunction that occurs in patients with chronic viral hepatitis C, there are attempts by researchers to supplement the antiviral effect of standard therapy with α-interferon by including immunotropic drugs in the treatment regimen. So in the method of treatment of HVHS proposed by Mitsura V.M. et al., a combination of α-interferon with the immunotropic drug Roncoleukin® is used, which is prescribed for the first 8 weeks at 500 mg 2 times a week, intravenously in 400 ml of 0.9% sodium chloride solution for 5 hours, a total of 16 administrations [4, 5 ]. However, with this method of administration of roncoleukin, a number of difficulties arise in the conduct of therapy (many hours of intravenous infusion) and all side effects inherent in the group of interferons are preserved.

There is also a known method for the treatment of HCV, proposed by Sklar L.F., a combination of intravenous administration of the drug Roncoleukin ^® with oral administration of corbiculin [6]. The effectiveness of this treatment method is lower than standard treatment with interferon-type drugs. In addition, just as in the above method, the inconvenience of the dosage form of roncoleukin (many hours of intravenous infusion) remains.

Both of the above methods do not solve the main task of treating chronic viral hepatitis C - the prevention of relapse. Their immunotropic effect is limited in time - the duration of one course of administration of the drug Roncoleukin ^® . Given the tropicity of hepatitis C virus to the cells of the immune system, patients with the formed CVHC should be considered as immunocompromised individuals, which is confirmed by studies conducted in various phases of chronic viral hepatitis C (including in the remission phase). Therefore, in order to ensure stable remission, it is necessary to carry out immunorehabilitation for several years, taking into account the data of the immune examination. The lack of further dynamic monitoring of the state of the immune system and supporting courses of immunocorrective effects does not protect patients with chronic viral hepatitis C from late relapses.

The aim of the invention is to prevent the recurrence of chronic viral hepatitis C after achieving primary virological remission.

This goal is achieved by the fact that after interferon therapy, roncoleukin is administered at a dose of 500 mg orally in 200 ml of water after dinner, in two courses, 5-10 times every other day or 2 times a week, after the third administration of roncoleukin, 10 mg of lycopide is additionally administered daily 1 time per day for 10 days with an interval between courses of 2 months, if necessary, repeat the courses.

Roncoleukin ^® is a recombinant human interleukin-2, a structural and functional analogue of endogenous human interleukin-2. Interacting with receptors, induces the growth, differentiation and proliferation of T and B lymphocytes, monocytes, macrophages, oligodendroglial cells, epidermal Langerhans cells. Stimulates the cytolytic activity of natural killers and cytotoxic T-lymphocytes. Provides immune defense in case of bacterial, viral, fungal, oncological aggression [5, 7].

As a synergistic immunocorrective drug, we included Likopid (GMDP), which is a universal component of the bacterial wall and is a natural stimulant of the human immune system (non-specific vaccine), while Roncoleukin acts as its biological adjuvant.

The novelty of this method of treatment for HCVH is as follows:

1) for the first time in chronic hepatitis C, the drug Likopid (GMDP) is used to prevent relapse of the disease;

2) for the first time in chronic hepatitis C, the drug roncoleukin ^{® is} used as a biological adjuvant cyclically, first with two courses of 5-10 injections (depending on the depth of the detected immune imbalance) with an interval of 2 months, then the courses are repeated in spring and autumn;

3) for the first time in chronic hepatitis C, the introduction of the drug Roncoleukin ^® 500 mg is administered orally in 200 ml of water;

4) treatment is carried out after the achievement of primary virological remission in individuals with the presence of immune deficiency.

Among the outpatients with chronic hepatitis C, dynamically observed in the Regional Hepatology Center of the city of Samara, after completion of the course of antiviral therapy and achievement of primary virological remission, immunological examination revealed patients with immune deficiency.

All patients were comprehensively examined using clinical and laboratory-instrumental research methods. The diagnosis of CVHC was confirmed by the detection of specific antibodies in the blood serum to HCV antigens (anti-HCV IgG, anti-HCV total) and RNA by the HCV polymerase chain reaction (PCR) method with determination of the viral load genotype (semi-quantitative method). The degree of disease activity was determined on the basis of clinical and biochemical data. The study of the immune status was carried out by the method of indirect immunofluorescence using monoclonal antibodies to (series IKO production MedBioSpektr) CD3, CD4 ⁺ , CD8 ⁺ , CD16 ⁺ , CD20 ⁺ - differentiation antigens. Determination of immunoglobulins A, M, G - by the method of radial immunodiffusion according to Mancini. The phagocytic activity of leukocytes (F.A.L.) was evaluated by the ability of neutrophilic granulocytes in the blood to absorb polystyrene latex particles. The circulating immune complexes (CEC) were determined by the method of deposition of polyethylene glycol M.m. 6000 (Yu.A. Grinevich, A.N. Alferov, 1981). The hemolytic activity of the complement system was evaluated by 50% hemolysis (CH50)

The study included 31 patients with chronic hepatitis C virus infection (men - 17, women - 14), the age of the patients was 20-47 years. The estimated duration of infection was 2-12 years (up to 5 years - 64%, over 5 to 10 years - 30%, more than 10 years - 6%). According to PCR, the 1c HCV genotype prevailed, accounting for 54%, the 3a genotype was detected in 42%, in the remaining cases 2 genotypes were detected or HCV RNA was not typed. The observation period for patients of all groups ranged from 6 months to 18 months after the end of antiviral therapy.

According to the methods of achieving virological remission and further treatment therapy, patients were divided into the following 3 groups:

I. Patients after completing the course of "standard" antiviral therapy with a drug from the group of α-interferons (reaferon-EC) 3 million ME 3 times a week in the muscle or under the skin for 6-12 months, receiving only symptomatic therapy (11 patients )

II. Patients who, after completion of therapy with a combination of α-interferon, 3 million ME 3 times a week in a muscle or under the skin with an immunotropic drug Roncoleukin ^® , which is prescribed for the first 8 weeks, 500 mg 2 times a week, intravenously, in a drop of 400 ml of 0.9% sodium chloride solution for 5 hours, a total of 16 injections, also received only symptomatic therapy (9 people).

III. Patients who received a course of standard antiviral therapy with a drug from the group of α-interferons (reaferon-EC) 3 million ME 3 times a week in the muscle or under the skin for 6-12 months, after completion of treatment received further Roncoleukin ^® 500 mg orally in 200 ml of water in three courses 5-10 times every other day, after the third dose, Likopid 10 mg was taken once a day for 10 days. The interval between courses is 2 months (11 people).

Results.

Clinical and laboratory examination data in patients of all three groups at the time of inclusion in the observation group were comparable. The most characteristic signs of the disease were: minor manifestations of astheno-vegetative and dyspeptic syndromes, which were recorded in 24% -32% of cases. For dyspeptic syndrome, the most characteristic signs were flatulence (18-25%), bitterness and dry mouth (10-17%), decreased appetite (6-10%). Often revealed the syndrome of the right hypochondrium (severity, aching pain, discomfort), which was recorded in 24-32% of cases.

An objective examination of most patients showed extrahepatic biliary signs (palmar erythema, vascular "stars" on the skin of the chest). In single patients of all four groups, scleric subtericosis, hemorrhagic syndrome, in the form of bloody crusts in the nose, were noted. An increase in the liver (from 1.0 to 3.0 cm) was observed in 72-80% of patients. The spleen was enlarged in 7-9% of cases.

The results of biochemical examination of patients were as follows. In 9-11% of patients, moderate pigment metabolism was observed - an increase in bilirubin to 27 μmol / L, mainly due to the free fraction. The cytolysis activity in terms of AlAt and GGTP was higher than normal in isolated cases, which did not significantly differ from the parameters of healthy individuals. Functional liver tests characterizing the state of lipid metabolism (β-lipoproteins, cholesterol) were moderately altered (above or below normal) in patients of all groups in 9-22% of cases. The revealed changes did not differ significantly from the values in the group of healthy individuals. Indicators of mesenchymal-inflammatory syndrome (thymol test, gamma globulin) were moderately increased in patients of all 3 groups.

The data of virological examination (PCR) corresponded to the phase of remission of chronic viral hepatitis C.

Results of a virological examination.

In patients of all observation groups, against the background of normocytosis (tendency to leukopenia), relative lymphocytosis was recorded in half of the cases (p <0.001).

The most frequent and pronounced changes in the immune status were recorded in the T-cell immunity (CD4 ⁺ ; CD8 ⁺ ) and the natural killer system (CD16 ⁺ ). Of particular note is the fact that in the remission phase with minimal clinical and laboratory changes, more than half of the patients maintained an imbalance of T and NK lymphocytes (p <0.05). Increased CEC values and decreased activity of the complement system were also recorded in all 3 groups.

Patients of all groups were observed for at least 6 months. In group 1, an exacerbation of the disease was observed in 6 patients, in group 2 - in 3, which amounted to 54% in the 1st group achieving stable remission, and 66% in the 2nd group. In group 3 - only in three patients with a virological examination revealed a relapse of the disease (73% - stable remission). As a rule, aggravation of the disease was preceded by provoking factors - an error in the diet, psycho-emotional stress, a change in the climatic zone. In 2 patients, the recurrence of chronic viral hepatitis C was preceded by an exacerbation of chronic cholecystitis and pancreatitis (bitterness, dry mouth, heaviness in the right hypochondrium, the appearance of soreness at the point of the gallbladder and choledochopancreatic zone), an increase in AlAt was subsequently recorded (up to 2-4- x norms) and a change in other functional liver tests.

The claimed method of treatment is illustrated by the following examples.

Example 1

Patient S., 27 years old, outpatient card No. 48, diagnosis: chronic viral hepatitis C (HCV RNA neg.), Without signs of activity of the process, outside the virus replication. It has been under the supervision of the Regional Hepatology Center since 2004, when chronic viral hepatitis C (HCV + RNA, 3a), a low degree of activity of the process (according to the degree of cytolysis) and initial signs of liver fibrosis (according to ultrasound), with a high viral load (for the first time) were first detected. 1:10 ⁴ ). Revealed chronic cholangiocholecystitis with the phenomena of mixed biliary dyskinesia. Sick for 7 years (severe asthenovegetative syndrome, arthralgia, periodic heaviness in the right hypochondrium, bitterness in the mouth).

From January 2005 to January 2006 (12 months), a course of antiviral therapy with EU reaferon in the muscle was carried out at a dose of 3 million ME 3 times a week with the achievement of clinical, biochemical and virological remission.

At the end of treatment, an objective examination revealed moderately pronounced extrahepatic biliary signs (palmar erythema, single mild vascular "stars"). The liver protrudes from the edge of the costal arch by 1 cm, dense, painless.

Functional liver tests: bilirubin - 14 μmol / l (normal), alanine aminotransferase - 18.7 (normal), thymol test - 4.5 units (0-4 units), moderate dysproteinemia with a decrease in albumin to 52.8 (56-57) g / l) and an increase in γ-globulins to 23.3% (12.8-19.0%). In a general blood test - without pathology. Immunogram from 11/7/05: white blood cells - 4.0 × 10 ⁹ (normal), relative lymphocyte values - 32% (normal), absolute 1.3 × 10 ⁹ (normal), subpopulation of CD3 + lymphocytes relative 44% (normal 60- 80%), absolute 0.6 × 10 ⁹ (norm 0.8-2.2 × 10 ⁹ ), subpopulation of CD4 + lymphocytes relative 32% (norm 35-50%), absolute 0.4 × 10 ⁹ (norm 0 , 6-1.6 × 10 ⁹ ), values of a subpopulation of lymphocytes CD8 + relative 12% (norm 19-40%), absolute 0.15 × 10 ⁹ (norm 0.3-0.8 × 10 ⁹ ), values of a subpopulation of lymphocytes CD16 + relative 3% (10-20%), absolute 0.04 × 10 ⁹ (0.2-0.4 × 10 ⁹ ), values of a subpopulation of lymphocytes CD20 + include 6% (5-16%), absolute 0.08 × 10 ⁹ (0.15-0.5 × 10 ⁹ ), immunoregulatory index - 2.0 (normal), immunoglobulins: A - 1.4 (normal) , G - 15.7 (normal), M - 1.5 (normal), leukocyte phagocytic activity 41% (normal), circulating immune complexes - 85.0 (normal), complement activity CH-50 - 53 (normal), RNA HCV neg.

Taking into account the revealed changes in the immune status corresponding to the combined deficit of the relative and absolute values of the subpopulations of T-lymphocytes and NK cells, Roncoleukin ^® was administered at a dose of 500 mg in order to immunocorrect the revealed violations, which was taken orally in 200 ml of water, 2 hours after dinner, in two courses of 5 doses every other day, after the third dose, Likopid 10 mg was taken daily 1 time per day for 10 days. The interval between courses is 2 months, then another 5 receptions 2 times a week, two courses with an interval of 2 months. The course of treatment was completed in May 2006.

In the absence of clinical and biochemical signs of exacerbation of CVHC and virus replication (HCV RNA neg.), The phenomena of immune deficiency disappeared in the immunogram: leukocytes - 6.3 × 10 ⁹ (normal), relative lymphocyte values - 43% (normal), absolute 2.7 × 10 ⁹ (normal), subpopulation of CD3 + lymphocytes relative 70% (normal), absolute 1.9 × 10 ⁹ (normal), subpopulation of CD4 + lymphocyte relative 47% (normal), absolute 1.2 × 10 ⁹ (normal) values subpopulation of CD8 + lymphocytes relative 18% (lower limit of normal), absolute 0,5 × ¹⁰ September (norm) values SMS ulyatsii relative lymphocytes CD16 + 15% (normal), absolute September ¹⁰ 0,4 × (upper limit of normal), the values of lymphocytes CD20 + subpopulation relative 8% (normal), absolute 0,2 × ¹⁰ September (normal), immunoglobulins: A - 3 5 g / l (normal), G - 19.5 (normal), M - 1.8 (upper limit of normal), leukocyte phagocytic activity 68% (normal), circulating immune complexes - 97.2 (normal), activity complement 55.2 (upper limit of normal).

Subsequently, during dynamic clinical and laboratory observation for another 6 months (until January 2007), there were no clinical, biochemical and virological signs of recurrence of CVHC, during the observation period there was no exacerbation of chronic cholangiocholecystitis. There were no signs of immune deficiency in the immunogram: leukocytes - 4.3 × 10 ⁹ (normal), relative lymphocyte values - 38% (normal), absolute 1.6 × 10 ⁹ (normal), CD3 + lymphocyte subpopulation values - relative 78% (normal) absolute 1.2 × 10 ⁹ (normal), values of a subpopulation of CD4 + lymphocytes relative 38% (normal), absolute 0.6 × 10 ⁹ (normal), values of a subpopulation of CD4 + lymphocytes relative 40% (normal), absolute 0.4 × 10 ⁹ (normal), values of a subpopulation of lymphocytes CD16 + relative 16% (normal), absolute 0.3 × 10 ⁹ (normal), values of a subpopulation of lymphocytes CD20 + о relative 16% (normal), absolute 0.3 × 10 ⁹ (normal), immunoglobulins: A - 1.6 g / l (normal), G - 15.7 (normal), M - 1.5 (upper limit of normal) ), phagocytic activity of leukocytes 59% (normal).

Example 2

Patient K, 25 years old, outpatient card No. 34. Diagnosis: chronic viral hepatitis C with a low degree of activity of the process, outside the phase of virus replication (HCV RNA neg.), Without exacerbation.

Has been observed in the Regional Hepatology Center since 2005 with a diagnosis of chronic viral hepatitis C (RNA +, genotype 1c, 1:10 ³ ), a low degree of activity of the process, the phase of virus replication. The probable duration of infection is 1998 (single episodes of intravenous drug use). In recent years (5-6 years), periodic pains in the right hypochondrium, bitterness in the mouth, increased fatigue, and manifestations of an allergic syndrome (allergy to cat hair) began to disturb.

From August 2005 to July 2006 (12 months) a course of antiviral therapy with EU reaferon in the muscle was carried out at a dose of 3 million ME 3 times a week with the achievement of clinical and virological remission. The entire treatment period and at the time of the end of therapy maintained a moderate cytolytic syndrome (the value of alanine aminotransferase was increased by 2–3 times), which was probably due to the presence of an autoimmune syndrome during cytokine therapy.

After completion of etiotropic treatment, insignificant asthenovegetative syndrome persisted, examination revealed moderately pronounced extrahepatic biliary signs (palmar erythema, single mild vascular "stars"). The liver protrudes from under the edge of the costal arch by 1.0 cm, dense, slightly painful on palpation.

Functional liver tests: bilirubin - normal (free), alanine aminotransferase - 2 times higher than normal, thymol test - normal, alkaline phosphatase - normal, β-lipoproteins - 3.2 g / l (3.5-6.5 g / l ) moderate dysproteinemia (hypoalbuminemia - 51.4% at a rate of 57-67%; hypergammaglobulinemia - 22.8% at a rate of 12.8-19%). General blood test and general urine analysis without pathology. According to ultrasound: moderate diffuse changes in the liver parenchyma without signs of portal hypertension. Immunogram: white blood cells - 3.1 × 10 ⁹ (norm 4.0-9.0 × 10 ⁹ ), relative lymphocytes - 30% (norm), absolute 0.9 × 10 ⁹ (norm 1.2-3.0 × 10 ⁹ ), subpopulation of CD3 + lymphocytes relative 72% (normal), absolute 0.6 × 10 ⁹ (normal 0.8-2.2 × 10 ⁹ ), subpopulation of CD4 + lymphocytes relative 42% (normal), absolute 0.37 × 10 ⁹ (0.6-1.6 × 10 ⁹ ), subpopulation of CD8 + lymphocytes relative 24% (normal), absolute 0.2 × 10 ⁹ (normal 0.3-0.8 × 10 ⁹ ), lymphocyte subpopulation CD16 + relative 14% (norm), absolute 0.12 × 10 ⁹ (norm 0.2-0.4 × 10 ⁹ ), subpopulation of CD20 + lymphocytes relates. 12% (normal), absolute 0.1 × 10 ⁹ (0.15-0.5 × 10 ⁹ ), immunoregulatory index 1.75 (normal), immunoglobulins: A - 1.93 (normal), G - 13, 01 (normal), M 0.5 (0.6-3.0), leukocyte phagocytic activity 64% (normal), circulating immune complexes - 97% (normal), complement activity of CH-50 - 45.6 (48- 55).

The revealed changes in the immune status corresponded to insufficiency of the cellular component of immunity: absolute values of T-lymphocytes (CD3 +, CD4 +, CD8 +) and NK-cells content were reduced by 40% from the norm. A slight decrease in M immunoglobulins and compliment system proteins.

In connection with the detected (clinically and laboratory) immune deficiency, Roncoleukin ^® was prescribed at a dose of 500 mg, which was taken orally in 200 ml of water, 2 hours after dinner, in two courses of 5 doses every other day, then 5 more doses 2 times per week, after the third dose, Likopid 10 mg was taken daily 1 time per day for 10 days. The interval between courses is 2 months with two courses with an interval of 2 months. Tolerance is satisfactory. Side effects were not observed. After the treatment, the manifestations of asthenovegetative syndrome disappeared, with further observation for six months, exacerbations of chronic cholecystitis were not detected, allergy symptoms decreased, functional liver tests normalized: bilirubin 19.2 mmol / l (normal), alanine aminotransferase - 12.7 μmol / l ( normal), β-lipoproteins - 4.4 g / l (normal), albumin - 57% (lower limit of normal), gamma globulins - 19.1% (normal).

The values of the indicators of the immunogram: white blood cells - 7.0 × 10 ⁹ (normal), relative lymphocytes - 18% (lower limit of normal), absolute 1.1 × 10 ⁹ (lower normal limit), subpopulation of lymphocytes CD3 + relative 68% (normal), absolute 0.7 × 10 ⁹ (normal 0.8-2.2 × 10 ⁹ ), subpopulation of CD4 + lymphocytes relative 43% (lower limit of normal), absolute 0.6 × 10 ⁹ (normal), subpopulation of CD8 + lymphocytes relative 40% (norm), absolute 0.4 × 10 ⁹ (norm), subpopulation of CD16 + lymphocytes relative 18% (norm), absolute 0.28 × 10 ⁹ (norm), subpopulation of CD20 + lymphocytes relative 16% (norm), absolute 0.16 × 10 ⁹ (normal), immunoregulatory index - 1.2 (normal), immunoglobulins: A - 2.2 (normal), G - 16.0 (normal), M - 0.69 (normal), leukocyte phagocytic activity 63% (normal), circulating immune complexes - 99% (normal).

Using the proposed method can improve the quality and effectiveness of the treatment of chronic viral hepatitis C, avoids relapse of the disease and to eliminate the effects of immune deficiency.

The method is advisable to use in the treatment of chronic viral hepatitis C on an outpatient basis.

Information sources

1. Zhurkin A.T. Viral hepatitis. Textbook allowance. - SPb., 2004, 62 p.

2. Roncoleukin immunotherapy of chronic viral hepatitis C. Method, rivers. sost .: Sklyar L.F., Ivanis V.A., Markelova E.V. // Vladivostok, 2003-36 p.

3. Lobzin Yu.V. Infectious Disease Guide. - SPb .: Foliant Publishing House, 2000. - 936 p.

4. Mitsura V.M., Zhavoronok S.V., Krasavtsev E.L. The use of Roncoleukin in the treatment of chronic hepatitis C. Method, rivers. // Gomel, 2004.34 s.

5. Radchenko V.G. et al. The basics of clinical hepatology. Diseases of the liver and biliary system. - SPb .: Publishing House Dialect; M .: 2005. - 864 p.:

6. RF patent No. 2265447 dated 05/19/2004. A method for the treatment of chronic viral hepatitis.

7. Podymova S.D. Liver disease. - M.: Medicine, 1998, 704 p.

8. Popovich A.N., Egorova V.N. Interleukin 2: clinical experience. (second edition) - St. Petersburg: Publishing House Publishing House Law and Order News, 2006. - 36 pp., ill.

Claims (1)

A method for the prevention of recurrence of chronic viral hepatitis C after achieving primary virological remission using standard interferon therapy, characterized in that after interferon therapy, 500 mg of roncoleukin is administered orally in 200 ml of water after dinner, in two courses, 5-10 times every other day or 2 times a day a week, after the third administration of roncoleukin, lycopid 10 mg is additionally administered daily 1 time per day for 10 days, with an interval between courses of 2 months, if necessary, the courses are repeated.